Atrial fibrillation and sinus node dysfunction in human ankyrin-B syndrome: a computational analysis

Abstract

Ankyrin-B is a multifunctional adapter protein responsible for localization and stabilization of select ion channels, transporters, and signaling molecules in excitable cells including cardiomyocytes. Ankyrin-B dysfunction has been linked with highly penetrant sinoatrial node (SAN) dysfunction and increased susceptibility to atrial fibrillation. While previous studies have identified a role for abnormal ion homeostasis in ventricular arrhythmias, the molecular mechanisms responsible for atrial arrhythmias and SAN dysfunction in human patients with ankyrin-B syndrome are unclear. Here, we develop a computational model of ankyrin-B dysfunction in atrial and SAN cells and tissue to determine the mechanism for increased susceptibility to atrial fibrillation and SAN dysfunction in human patients with ankyrin-B syndrome. Our simulations predict that defective membrane targeting of the voltage-gated L-type Ca(2+) channel Cav1.3 leads to action potential shortening that reduces the critical atrial tissue mass needed to sustain reentrant activation. In parallel, increased fibrosis results in conduction slowing that further increases the susceptibility to sustained reentry in the setting of ankyrin-B dysfunction. In SAN cells, loss of Cav1.3 slows spontaneous pacemaking activity, whereas defects in Na(+)/Ca(2+) exchanger and Na(+)/K(+) ATPase increase variability in SAN cell firing. Finally, simulations of the intact SAN reveal a shift in primary pacemaker site, SAN exit block, and even SAN failure in ankyrin-B-deficient tissue. These studies identify the mechanism for increased susceptibility to atrial fibrillation and SAN dysfunction in human disease. Importantly, ankyrin-B dysfunction involves changes at both the cell and tissue levels that favor the common manifestation of atrial arrhythmias and SAN dysfunction.

Effects of Wild-Type and Mutant Forms of Atrial Natriuretic Peptide on Atrial Electrophysiology and Arrhythmogenesis

“…4,33,51,52 Reductions in wavelength that favor the occurrence of AF are commonly associated with changes in ion-channel function or regulation in atrial myocytes. [53][54][55] Our novel studies demonstrate that mANP decreases APD (which corresponds to a reduction in atrial refractory period) and V max (which is consistent with the slowing of atrial CV). In agreement with these findings, direct assessment of refractoriness in intact atrial preparations illustrates that mANP shortened atrial ERP.…”

Two‐Pore K + Channel TREK‐1 Regulates Sinoatrial Node Membrane Excitability

“…Computer code was written in C++ and compiled using Intel Composer XE 2011 for Linux. Computer simulations were performed on a Dell PowerEdge R515 server (dual 6 core, 32 GB RAM running CentOS 6.2), as described 21, 22, 27, 28, 29, 30. Regression was performed using MATLAB R2014b (MathWorks) on a MacBook Pro with a 2.5‐GHz Intel Core i7 processor (Apple Inc).…”

The evolving role of ankyrin-B in cardiovascular disease

“…Heterozygosity of AnkB in mouse sinoatrial node and atrial myocytes is associated with reduced expression of 12, 32 Additionally, Ca v 1.3.cardiac-specific deletion of EHD3 results in dysregulated expression and localization of Ca v 3.1 and Ca v 3.2 and reduced T-type mediated Ca 2+ current. 33 AnkB +/− mice display sinus node and atrial electrophysiological dysfunction, abnormal SAN electrical activity (including altered diastolic depolarization), shortened atrial action potentials, atrial fibrosis, and increased susceptibility to atrial fibrillation.…”